tbuckley/cabot-search huggingface dataset:
OTHR-43. Composition of cell-free miRNA in cerebrospinal fluid and plasma as a monitoring tool for pediatric brain tumors
Authors: Coyle Anne, Madison Hollawell, Komal Rathi, Christopher Beck, Namrata Choudhari, Tiffany Smith, Madsen Peter, Phillip Storm, Adam Resnick, Jessica Foster, Mateusz Koptyra
Journal: Neuro-Oncology (2022)

Abstract Current clinical management of pediatric brain tumor patients involves non-invasive imaging studies to monitor therapeutic response and tumor progression. However, results are often inconclusive and unable to capture biological changes that presage progression on imaging. Non-invasive diagnostics, also termed liquid biopsy, have emerged for detection of cell-free cancer material but there are no such standard, clinically defined biomarkers or methods for pediatric brain tumors. Circulating miRNA presents an attractive biomarker platform given its stability in bio-fluids, selective expression in tumors and release from tumor cells into the extracellular environment. Technology development has permitted high throughput analysis of material obtained from biofluids including plasma and cerebrospinal fluid (CSF). We performed miRNA profiling across a cohort of 54 pediatric brain tumors from different histologies (low grade glioma, ependymoma, germinoma, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma) using CSF (33) and plasma (53) with HTG EdgeSeq platform. CSF and plasma specimens clustered independently of each other providing separate biomarker platforms. Consensus clustering performed on CSF specimens revealed clusters correlated with disease severity (tumor grade). We identified miRNA targets closely correlated with tumor grade (p&amp;lt;0.001), tumor dissemination or metastases (p&amp;lt;0.001) and survival (p=0.001). Similarly in plasma, through consensus clustering we identified cohorts with correlation to tumor grade. While distinct from those identified in CSF, specific plasma miRNA also correlated with clinical (tumor grade; p&amp;lt;0.001, dissemination or metastasis; p=0.002) and demographic (gender; p=0.001) features. Independently, histology-specific miRNA signature was also identified for low grade glioma, medulloblastoma and germinoma in plasma and CSF. The results present differential expression of cell-free miRNAs in plasma and CSF as biomarkers associated with diverse clinical diagnostic and prognostic measures. Further utilization of this approach provides unique platforms (plasma and/or CSF) to inform liquid biopsy-based management in the clinical setting.
TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes
Authors: Manu Verma, Nellie Y. Loh, Rugivan Sabaratnam, Senthil K. Vasan, Andrea D. van Dam, Marijana Todorčević, Matthew J. Neville, Enrique Toledo, Fredrik Karpe, Constantinos Christodoulides
Journal: Metabolism (2022)
Serum concentrations of oncometabolite, 2-hydroxyglutarate (2HG), as biomarkers for isocitrate dehydrogenase <i>(IDH1/2</i>) mutations in cholangiocarcinoma (ICCA).
Authors: Cha Len Lee, Warren P. Mason, Grainne M. O'Kane, Robert C. Grant, Jennifer J. Knox, Candice Cruz, Wenjiang Zhang, Gelareh Zadeh, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2022)

3049 Background: Mutations in IDH1/2 genes are common in low-grade glioma (GM) and occur in approximately 20% of intrahepatic cholangiocarcinoma (ICCA). Mutant IDHs leads to preferential accumulation of the R-relative (R2HG) to the S-enantiomer (S2HG) of 2HG. We investigated the utility of circulating R2HG, total R2HG+S2HG (tRS) and ratio of R2HG/S2HG (rRS) as biomarkers in GM and ICCA patients (pts). Methods: Blood and tumor tissues samples were obtained from pts with IDH1/2-mutant GM and ICCA. IDH mutation was confirmed by either immunohistochemistry (GM pts) or next generation sequencing (ICCA pts). Samples were analyzed for S2HG and R2HG using a validated HPLC tandem mass spectrometry method. Tissue and serum R2HG, tRS and rRS were compared with paired t-tests for GM pts. Serum S2HG, R2HG, tRS and rRS were compared with unpaired t-tests between GM and ICCA pts. A p&lt;0.05 was considered statistically significant. Results: Blood and tumor samples were collected from 21 pts (GM = 11, ICCA=10). Tumor tissues were insufficient for analysis in 1 GM and 8 ICCA pts. Tissue S2HG, R2HG, tRS, and rRS were 0.72±0.68 ng/g, 48.92±58.92 ng/g, 66.87±80.35 ng/g and 55.77±36.23 for GM pts. There were no differences in R2HG and tRS between tissue and serum samples, while S2HG was significantly higher in serum samples ( p = 0.001) and rRS was significantly higher in tissue samples for GM pts ( p = 0.001). rRS were 144.8 and 244.9 respectively in 2 ICCA pts with sufficient tissues. There was no difference in serum S2HG between GM and ICCA pts. However, serum R2HG, tRS and rRS were significantly higher in ICCA pts. Conclusions: In IDH1/2 mutant GM and ICCA pts, R2HG was increased relative to S2HG in tumor tissues. In GM pts, the accumulation of R2HG in tumor tissues was not reflected in blood, likely due to the inability of 2HG to diffuse across the blood-brain barrier. Serum R2HG, tRS and rRS were significantly elevated in ICCA pts. These biomarkers have no clinical utilities in GM pts. However, they can potentially be used to identify IDH mutations in ICCA pts, especially given the inability to obtain tumor tissue in some ICCA pts. Clinical trial information: NCT03991832. [Table: see text]
Updated FDA pooled analysis of pain medication use in trial participants with HR+, HER2-negative metastatic breast cancer treated with endocrine therapy and a CDK 4/6 inhibitor.
Authors: Jennifer J Gao, Andrew Girvin, Christine Hodgdon, Christy Osgood, Gwynn Ison, Vishal Bhatnagar, Paul Gustav Kluetz, Richard Pazdur, Laleh Amiri-Kordestani, Julia A. Beaver
Journal: Journal of Clinical Oncology (2022)

e24101 Background: Pain medications (PMs) are commonly used to treat pain in patients with advanced or metastatic breast cancer (MBC). We previously reported an initial analysis of PM prescribing patterns in clinical trial participants with breast cancer receiving CDK 4/6 inhibitor (CDKI)-based treatment. We present an updated analysis here. Methods: We pooled data from 7 randomized controlled trials of CDKI + endocrine therapy (ET) in patients with HR+, HER2-negative MBC. All analyzed patients received at least 1 dose of CDKI/placebo+ET and a concomitant PM with a documented start date. Medications administered during hospitalizations were not included. We looked at PM use in all patients, patients who took PM only before or after the trial started, and those who took PM both before and during the trial. PMs were categorized as opioid (includes codeine-containing), NSAIDS, or other (i.e. bone-directed, antiepileptic, topical PMs). Results: 4200 patients enrolled across the 7 trials who received at least one dose of CDKI/placebo+ET (n = 2616 CDKI, n = 1548 placebo). Of these, 2881 took a PM at any time (n = 1774 CDKI, n = 1107 placebo). Of the 1774 patients who received CDKI+ET, 487 (27%) took at least one opioid and one NSAID at any time, 782 (44%) took at least one NSAID at any time but no opioids, 244 (14%) took at least one opioid at any time but no NSAIDs, and 261 (15%) took only PM that were not opioids or NSAIDs. Of the 1107 patients who received placebo+ET, 297 (27%) took at least one opioid and one NSAID at any time, 490 (44%) took at least one NSAID at any time but no opioids, 153 (14%) took at least one opioid at any time but no NSAIDS, and 167 (15%) took only PM that were not opioids or NSAIDs. Of the 2881 patients who took a PM at any time, 2038 patients (n = 1222 CDKI, n = 816 placebo) had documented start for their PM. Of these, 544 took PM only before the trial started (n = 334 CDKI, n = 210 placebo), 915 took a PM only during the trial (n = 551 CDKI, n = 364 placebo), and 579 took a PM both before and during the trial (n = 337 CDKI, n = 242 placebo). Overall, more patients took NSAIDs only compared to opioids only. Patient characteristics at baseline were balanced between the two arms. Conclusions: Overall, PM prescribing patterns were similar between the arms. NSAID use was higher than opiates in all groups. These findings are hypothesis generating and additional research is needed to determine the impact of PM on participants’ pain and physical function. Further research should include an understanding of the duration of PM needed in patients with MBC.
Odds of stage IV bone cancer diagnosis based on socioeconomic and geographical factors.
Authors: Kevin McMahon, Vincent Eaton, Connor Tupper, Matthew Morris, Matthew Merwin, Kishan Srikanth, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2022)

e23506 Background: There are significant differences in prognosis for osteosarcoma, Ewing Sarcoma, chondrosarcoma, &amp; chordomas based on stage at diagnosis. 5-year survival at early stage vs late stage is as follows; osteosarcoma 75% vs 27%, Ewing sarcoma 82% vs 39%, chondrosarcoma 78% vs 22%, and chordomas 87% vs 55%. This study seeks to evaluate the socioeconomic and geographical factors that affect the odds of late-stage bone cancer diagnosis. Methods: This study retrospectively evaluated the risk of stage I vs stage IV cancer at diagnosis in patients with primary malignant bone tumors (osteosarcoma, chondrosarcoma, Ewing sarcoma &amp; chordoma) diagnosed and recorded in the National Cancer Database (NCDB) between 2004 and 2018. Patients were identified by ICD-O-3 codes and patients with other malignancies were excluded. Cross Tabulations with Chi-square analysis was performed to evaluate frequencies of different socioeconomic and geographical characteristics between groups. Multivariable binary logistic regression was performed to evaluate relationships between socioeconomic and geographical factors and the odds of stage IV cancer. Statistical significance was set at α = 0.05. Results: 11,945 patients with stage I or stage IV primary malignant bone tumors were identified. Odds of stage IV bone cancer at diagnosis increased in patients of greater age (odds ratio [OR] = 1.011, 95% confidence interval [CI]: 1.003-1.018). Odds of stage IV bone cancer at diagnosis were decreased with female sex (OR = 0.747, 95% CI: 0.647-0.862), private insurance (OR = 0.519, 95% CI: 0.367-0.732), Medicare insurance (OR = 0.664, 95% CI: 0.456-0.965), or with diagnosis at comprehensive cancer center programs (OR = 0.549, 95% CI: 0.371-0.814), academic/research programs (OR = 0.339, 95% CI: 0.232-0.495), or integrated cancer network programs (OR = 0.392, 95% CI: 0.261-0.587). No significant relationship was identified between stage at diagnosis and race, ethnicity, Charlson-Deyo score, income, education, region, travel distance, or urban/rural status. Conclusions: Odds of stage IV bone cancer at diagnosis are greater with increasing age, male sex, non-private or non-Medicare insurance status, or treatment at community cancer programs.
Accuracy of AUA and EAU risk stratification groups in predicting early recurrence in Hg Ta non-muscle invasive bladder cancer: A comparison analysis
Authors: R. Contieri, A. Gobbo, M. Paciotti, P.P. Avolio, V. Fasulo, C. Saitta, A. Uleri, M. Valeri, P. Colombo, A. Saita, M. Lazzeri, P. Casale, G. Lughezzani, N.M. Buffi, G. Guazzoni, R. Hurle
Journal: European Urology (2022)
Assessment of HER2 protein overexpression and gene amplification in renal collecting duct carcinoma: Therapeutic implication
Authors: M. Costantini, S. Sentinelli, L. Torregrossa, G. Alì, E. Munari, C. Jeronimo, R. Henrique, S. Petronilho, U. Capitanio, R. Lucianò, N. Suardi, M.T. Landi, U. Anceschi, A.M. Bove, A. Brassetti, M.C. Ferriero, R. Mastroianni, L. Misuraca, G. Tuderti, V.M. Fazio, M. Gallucci, G. Simone, M.L. Poeta
Journal: European Urology (2022)
PD-L1 immune cell expression levels and clinical outcomes in advanced triple-negative breast cancer treated with atezolizumab.
Authors: Tanja Ovcaricek, Luka Dobovisek, Gorana Gasljevic, Dimitar Stefanovski, Simona Borstnar
Journal: Journal of Clinical Oncology (2022)

e13066 Background: Treatment with immune checkpoint inhibitors (ICI) has become a standard of care for metastatic PD-L1 positive TNBC patients and PD-L1 has emerged as an important predictive biomarker. Predictive differences of PD-L1 were found in response to immunotherapy in different studies. Alterations in DNA repair pathways (aDDR) have also been investigated as a predictive biomarker for ICI due to the increased mutations and neoantigen production. Real-world data regarding outcomes of treatment of metastatic (m)TNBC patients (pts) with ICI and predictive value of PD-L1 and aDDR is lacking. In this study PD-L1 and aDDR were evaluated for association with clinical benefit of treatment with atezolizumab and nab-paclitaxel (A+nP) in PD-L1 positive mTNBC patients treated in routine clinical practice. Methods: Medical records from 41 PD-L1 positive mTNBC patients consecutively treated with A+nP at Oncology Institute Ljubljana between April 2019 and October 2021 were collected for the present study. PD-L1 expression was assessed on immune cells (IC) as percentage of tumor area using VENTANA SP142 PD-L1 IHC assay (&lt;1% [PD-L1 negative] vs. ≥1% [PD-L1 positive). Patients were divided into 2 subgroups based on PD-L1 status, high (PD-L1≥ 5%) and low (PD-L1 ≥1% and &lt;5%). Germline alteration status in DDR genes was determined on blood samples. We used Kaplan-Meier survival curves to calculate median (m) PFS and OS . The prognostic impact of PD-L1exspresion levels and aDDR was calculated using Cox model. Results: Median follow up of the study was 22 months. Majority of patients had low PD-L1 status (25/41, 61%) and 54% of evaluable patients (15/28) were found to harbor deleterious alterations in DDR genes, of them BRCA1 in 9 pts, BRCA2 in 2 pts, and PALB2, CHEK2, CHD1, RAD51D in 1 pts. Median PFS in the entire cohort was 8.26 months; 95% CI (3.54-12.98) and mOS 20.49 months; 95% CI (11.3-29.7). Significant survival benefit was observed among patients with high PD-L1 status treated with A+nP. No difference in survival was found in patients harbouring germline mutations (aDDR positive) versus without mutations (Table). Conclusions: PD-L1 positive mTNBC patients with high PD-L1 status (≥5%) had almost three times less risk of progression and death compared to low PD-L1 status (≥1% and &lt;5%). Presence of aDDR showed no effect on disease outcome. [Table: see text]
Persistence of overactive bladder pharmacological treatment in women as reflected from large-scale real-world data of prescription claims: A retrospective cohort study (2010-2020)
Authors: K. Lifshitz, I. Mintz, C. Shenhar, O. Yossepowitch, J. Baniel, Y. Shtabholtz, S. Aharony
Journal: European Urology (2022)
LINC-10. The Adequate Treatment of Children and Adolescents with Primary Central Nervous System Germ Cell Tumors (CNS GCT) in a Developing Country
Authors: Andréa M Cappellano, Natalia Dassi, Bruna Mançano, Sidnei Epelman, Daniela B Almeida, Sergio Cavalheiro, Patricia A Dastoli, Maria Teresa Seixas, Jardel M Nicácio, Marcos D Costa, Frederico A Silva, Simone S Aguiar, Carlos R Almeida Jr, Gustavo R Teixeira, Nasjla S Silva, Jonathan L Finlay
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Primary central nervous system germ cell tumors (CNS GCT) are a heterogeneous group of malignancies that can be divided into germinomas and non-germinomatous GCT (NGGCT), accounting for 2-3% of brain tumors in children/adolescents in the Western hemisphere. The study aim is to report the ability to adequately treat Brazilian patients with CNSGCT through a consortium protocol, reporting their treatment, response and survival. Methods: Since 2013, 58 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels ≤200mIU/ml (n=43), five of them between 100-200mIU/ml, received carboplatin/ etoposide (4 cycles) and NGGCT (n=15), received carboplatin/etoposide/cyclophosphamide (6 cycles), all followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous hematopoietic cell transplant (AuHCT) was undertaken for NGGCT slow responders. Results: Mean age 13.2 years, 42 males. Diagnosis was made by TM (n=19), surgery (n=25) and both (n=12). Two bifocal cases with negative TM and inconclusive biopsy were treated as germinoma. Primary tumor location was pineal (n=30), suprasellar (n=16), bifocal (n=11) and basal ganglia/thalamus (n=1). Eighteen had ventricular/spinal spread. Second-look surgery occurred in seven patients. For the germinoma group, 36 achieved complete responses (CR) after chemotherapy, seven showed residual teratoma/scar. For the NGGCT after 4/6 cycles, six patients showed CR, two failure/progression and seven partial responses (five with negative TM). Two with positive TM underwent AuHCT. Radiotherapy was utilized as described, except in three patients. Four NGGCT patients died (two disease progression, two other causes with no disease). Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 40 months, event-free and overall survival was 100% for germinoma and 64.5% NGGCT. Conclusion: The proposed treatment was feasible to be performed in a developing country, with suitable survival even with VFI dose reduction to 18Gy.
Fragement C Gamma receptor IIIa polymorphism is predictive of trastuzumab efficacy in the neoadjuvant setting of HER2-positive breast cancer patients.
Authors: Kaping Lee, Rongzhen Luo, Shusen Wang, Fei Xu
Journal: Journal of Clinical Oncology (2022)

e12607 Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the most important mechanisms of Trastuzumab. Fragement C Gamma receptor (FcγR) IIA and IIIA polymorphisms influence the affinity of immunoglobin G (IgG). Recently, FcγRIIA and FcγRIIIA polymorphisms have identified with the efficacy of trastuzumab. However, whether FcγR polymorphisms are associated with the efficacy of trastuzumab in the neoadjuvant setting was unclear. Methods: We retrospectively enrolled 101 patients with HER2-positive breast cancer receiving chemotherapy plus trastuzumab as neoadjuvant therapy and mastectomy in Sun Yat-sen university cancer center from May 2015 to March 2021. Among them, twenty patients were excluded because lacking of blood samples. Clinical and pathological characteristics, treatments and outcomes of patients were collected. We purified the genomic DNA from peripheral blood samples, performed nested polymerase chain reaction (PCR) and sanger sequencing to identify the polymorphisms of FcγRIIA(rs1801274) and FcγRIIIA(rs396991). Results: Patient samples (n=81) were successfully detected. No significant differences between FcγRIIA/FcγRIIIA genotypes and clinical characteristics, including age, clinical stage, menstrual status, molecular subtyping, treatment and pathological complete response (pCR) rate. In subgroup analyses, FcγRIIIA polymorphism was significantly correlated with pCR rate in the population who received paclitaxel plus trastuzumab therapy (n=34, P&lt;0.05). The Kaplan-Meier analyses showed that no significant difference in disease-free survivals (DFS) between FcγRIIA-131 H/H and R carriers genotype groups ( P=0.24), either that in the FcγRIIIA-158 F/F and V carriers genotype groups ( P=0.60). But the DFS in FcγRIIIA-158 V carriers genotype group were significant longer than that in FcγRIIIA-158 F/F genotype group in subgroup who received paclitaxel plus trastuzumab therapy (n=34, P=0.036), while that was not significant difference in patients with anthracycline-based treatment (n=47, P=0.248). DFS has not yet been reached. Conclusions: FcγRIIIA polymorphism is predictive of trastuzumab efficacy in the neoadjuvant setting of HER2-positive breast cancer patients who received paclitaxel plus trastuzumab therapy. Anthracycline-based treatment may improve the outcomes of HER2 positive breast cancer patients with FcγRIIIA-158 F/F genotype.[Table: see text]
Integrated tumor genomic and immune microenvironment analysis identifies predictive biomarkers associated with the efficacy of neoadjuvant therapy for triple-negative breast cancer.
Authors: Yanhui Zhu, Chaohu Pan, Hongfei Zhang, Gao He, Xiafei Yu, Xiaoli Cui, Junzhe Yang, Xiaoqiang Zhang, Edmond Gao, Xiaoan Liu
Journal: Journal of Clinical Oncology (2022)

e12592 Background: Although neoadjuvant chemotherapy (NAC) is currently the best therapy for triple-negative breast cancer (TNBC), resistance still occurs in a considerable proportion of TNBC patients, making it crucial to understand resistance mechanisms and identify predictive biomarkers for patient selection. Methods: Biopsy samples were collected from 21 patients with TNBC who underwent NAC. Whole-exome sequencing, targeted sequencing, and multiplex immunohistochemistry (mIHC) were carried out on the all clinical samples and used to identify and validate potential biomarkers associated with response to NAC. In addition, data on 190 TNBC patients who had undergone chemotherapy were obtained from The Cancer Genome Atlas (TCGA) and analyzed to further validate our findings. Results: Both the tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly higher in responders than in non-responders. Higher response rates and longer survival rates were observed in patients with higher TMB. Patients with higher ratios of CD8 to M2 macrophages had higher response rates and improved survival rates. Finally, integrated analysis demonstrated that the combination of TMB and the ratio of CD8 T cells to M2 macrophages could further distinguish responders from non-responders in both enrolled patients and from public data. Conclusions: The findings of this study indicated that the combination of TMB and the ratio of CD8 T cells to M2 macrophages may be a potential biomarker for improving the recognition of NAT responders, thereby providing a basis for developing precision NAT regimens.